Understanding the relationship of blood vessel glycocalyx structure and composition with permeability

人类胎盘是胎儿的重要器官；它保护胎儿免受有害的母体病原体和免疫细胞的伤害，同时从母亲向胎儿输送氧气和重要营养物质。它是胎盘绒毛，沐浴在母体血液中，可以直接吸收营养(图1a)。这些溶质必须穿过外部合体滋养层和下面的胎儿内皮才能进入胎儿血液(图1b)。这两层都提供了一系列的抵抗力；这里的病理导致胎儿生长受阻和后来的心血管疾病(胎儿疾病的起源)。LEACH实验室的初步研究表明，合体滋养细胞有一个广泛的糖帽层-潜在的第三层阻力(图1c)。图1a-胎盘绒毛，包含胎儿血管，沐浴在母体血液中；图1b-2层分隔母血；图1c-广泛的糖萼(绿色)覆盖所有胎盘绒毛的外层。注意：一些胎儿血管(红色)也有管腔糖萼。在其他系统中，内皮表面糖基化(GLX)层已被证明对溶质运输具有很大的阻力[1]。GLX携带负电荷，从而阻止带电的溶质。GLX已被证明通过eNOS和一氧化氮途径启动血管扩张，并改变血流[2]。因此，这个项目将提出的紧迫问题是：胎盘中这一层的功能是什么？它是否阻碍了溶质的传输或过滤了可能或可能不会通过的东西？它是否确保最大限度地扩张母体流向胎盘的血管，以实现最佳的营养输送？为了解决这些问题，该项目将研究正常妊娠和合并糖尿病(营养过剩；胎儿巨大儿)和先兆子痫(胎儿生长受限；高度应激；营养运输减少；eNOS减少)的胎盘糖萼的组成。使用共聚焦显微镜和原位质谱仪，糖唇覆盖率将与胎儿生长和母体并发症相关。体外灌流胎盘模型将被用来研究血流改变对标记亲水性溶质运输的影响，GLX覆盖率和成分的变化，eNOS和内皮黏附分子的改变。多普勒超声血管造影术将显示胎盘中母体和胎儿血流的变化。将探索关键基因的表观遗传学变化。这些数据将提供关于胎盘糖萼在调节营养转移和胎儿生长方面的作用的新知识。不同妊娠并发症中潜在的经胎盘营养转移的受损机制将被阐明，并导致减轻胎儿死亡和后来的心血管并发症的新方法。参考文献了解更多信息：1.M.Gouverneur B.van den Berg M.Nieuwdorp E.Stroes H.Vink血管保护特性：流体剪切应力的影响。内科杂志。Https://doi.org/10.1111/j.1365-2796.2006.01625.x2.N.L.皮林格(2017)。血管内皮细胞糖萼：基础科学和临床意义。麻醉和重症监护。Https://doi.org/10.1177/0310057X1704500305

The human placenta is an essential organ for the fetus; it protects the fetus from harmful maternal pathogens and immune cells whilst delivering oxygen and vital nutrients from the mother to the fetus. It is haemochorial- placental villi lie bathed in maternal blood and can directly take up nutrients (Fig 1a). These solutes have to cross an outer syncytiotrophoblast layer and an underlying fetal endothelium to enter fetal blood (Fig 1b). Both layers provide resistance in series; pathology here lead to compromised fetal growth and later cardiovascular disease (fetal origin of disease). Pilot studies in Leach lab demonstrated that the syncytiotrophoblast has an extensive glycocalyx layer- a potential third layer of resistance (Fig 1c).Fig 1a- Placental villi, containing fetal blood vessels, lying bathed in maternal blood; Fig 1b -2 Layers separate maternal and fetal blood; Fig 1c- An extensive glycocalyx (green) cover the outer lining of all placental villi. Note some fetal vessels (red) also have luminal glycocalyx. In other systems, the endothelial surface glycocalyx (GLX) layer has been proven to provide large resistance to solute transport [1]. GLX carry negative charge, which deter charged solutes. GLX has been shown to initiate vasodilation, via the eNOS and nitric oxide pathway and alter blood flow [2]. Thus, the urgent questions this project will ask are: What is the function of this layer in the placenta? Is it hindering solute transport or filtering what may or may not get across? Does it ensure maximal vasodilatation of maternal flow to the placenta for optimal nutrient delivery? To address these questions this project will look at the composition of the placental glycocalyx from normal pregnancies and those complicated by diabetes (overnutrition; fetal macrosomia) and preeclampsia (fetal growth restriction; high sheer stress; reduced nutrient transport; reduced eNOS). Using confocal microscopy and in situ mass spectroscopy, the glycocalyx coverage will be correlated with fetal growth and maternal complications. An ex vivo perfused placental model will be used toinvestigate effects of altered flow on transport of tagged hydrophilic solutes, changes in GLX coverage and composition, altered eNOS and endothelial adhesion molecules. Doppler ultrasound angiography will reveal changes in maternal and fetal blood flows in the placenta. Epigenetic alterations in key genes will be probed. The data will deliver new knowledge on the role of the placental glycocalyx in regulating nutrient transfer and fetal growth. The impaired mechanisms underlying trans-placental nutrient transfer in different pregnancy complications will be elucidated and lead to novel approaches to alleviating fetal demise and later cardiovascular complications.References to learn more:1. M. GOUVERNEUR B. VAN DEN BERG M. NIEUWDORP E. STROES H. VINK Vasculoprotective properties of the endothelial glycocalyx: effects of fluid shear stress. J of Internal Medicine. https://doi.org/10.1111/j.1365-2796.2006.01625.x2. N. L. Pillinger (2017). Endothelial Glycocalyx: Basic Science and Clinical Implications. Anaesthesia and Intensive Care. https://doi.org/10.1177/0310057X1704500305